The main aim of this research is to develop biodegradable macromolecular gadolinium (III) complexes as safe, effective MRI contrast agents for cancer imaging. Macromolecular agents have a prolonged plasma and tissue retention time and can preferentially accumulate in solid tumors because of the vascularity of malignant tumors and the hyperpermeability of tumor blood vessels. It has been demonstrated in the last decade that macromolecular contrast agents are superior in cancer detection and staging and neoplastic angiogenesis imaging to the low molecular weight MRI contrast agents used in clinics, and may have a potential for noninvasive imaging of cancer treatment response with MRI. However, the slow metal clearance and consequent toxic effects have limited the clinical development of macromolecular Gd(III) complexes. Innovative approaches are required to solve this problem. We intend to develop a new class of biodegradable macromolecular Gd(III) complexes, which can be degraded into smaller molecules by the biomolecules in the body, which can be readily cleared from the body after the MRI exams. Biodegradable structures will be designed and incorporated into the polymer backbones of macromolecular paramagnetic complexes. The structures can be cleaved by the biomolecules in the plasma, resulting in breakage of the macromolecules into smaller complexes that can be removed through renal glomerular filtration. This project includes feasibility (R21) and development (R33) phases. In the R21 phase, biodegradable macromolecular Gd(III) complexes will be designed and synthesized to demonstrate the feasibility of the novel agents. The physicochemical and biological properties including relaxivity, degradability, acute toxicity, in vivo clearance and contrast enhancement of the agents will be preliminarily evaluated. In the R33 phase, the structures of the agents will be optimized. Their NMRD profile, safety, in vivo clearance and contrast enhancement in cancer imaging will be evaluated in detail using in vitro and in vivo methods. A lead agent with low toxicity, appropriate in vivo retention time, acceptable in vivo clearance rate and effective contrast enhancement on cancer MR imaging will be selected for further preclinical and clinical development.